CS217948B1 - (6,11-Dihydrodibenzo (b, e) thiepin-11-yl) inethylamines - Google Patents

Abstract

The invention relates to new (6,11-dihydrodibenzo/b,e/thiepin-11-yl)methylamines with primary (amino), secondary (methylamino) and tertiary (dimethylamino) amino groups and their derivatives substituted in position 4 by a methoxy group, as well as their salts with pharmaceutically acceptable inorganic or organic acids. The substances according to the invention have antireserpine, locally anesthetic and spasmolytic activity, so that they are useful as pharmaceuticals. They can be prepared by the decomposition of the corresponding 6,11-dihydrodibenzo/bje/thiepin-1 1 -acetic acids by the Curtius method, i.e. by conversion to acid chlorides and azides, their rearrangement by heating with ethanol to the corresponding carbamates and then by hydrolysis of these carbamates (primary amines are obtained), reduction of the carbamates with lithium aluminum hydride (secondary amines are obtained) and methylation of the primary amines with formaldehyde and Ις/formic salt (tertiary amines are obtained). The obtained bases are converted to salts by neutralization with acids, preferably with hydrogen chloride.

Description

(54) (6,11-Dihydrodibenzo (b, e) thiepin-11-yl) inethylamines

The present invention relates to novel (6,11-dihydrodibenzo [b, e] thiepin-11-yl) methylamines having primary (amino), secondary (methylamino) and tertiary (dimethylamino) amino groups and derivatives thereof substituted at the 4-position with methoxy, as well as salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of the invention have antireserpine, locally anesthetic and spasmolytic activity, so that they are useful as medicaments.

They can be prepared by degradation of the corresponding 6,11-dihydrodibenzo [b] thiepine-11-acetic acids by the Curtie method, ie conversion to acid chlorides and azides, rearrangement by heating with atanol to the corresponding carbamates and then hydrolysis of these carbamates (yielding primary amines ), reduction of carbamates with lithium aluminum hydride (secondary amines are obtained) and methylation of primary amines with formaldehyde and Ις / formic acid (tertiary amines are obtained).

The bases obtained are converted into salts by neutralization with acids, preferably with hydrogen chloride.

The present invention relates to novel (6,11-dihydrodibenzo [b, e] thiepin-11-yl) methylamines in general.

Wherein R is hydrogen or methoxy and R and R are the same or different and are hydrogen or methyl, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula (I) and their salts have antireaerpine, locally anesthetic and spasmolytic activity, so that they are useful as medicaments in the treatment of mental depression, as an anesthetic for minor surgical procedures and finally as a means of releasing smooth muscle contractions, especially the gastrointestinal system. The relevant pharmacological properties of several of the compounds of the invention, as determined in tests on experimental animals or on isolated organs, are given below.

11- (Aminomethyl) -6,11-dihydrodibenzo [B, e] thiepine was tested in the form of hydrochloride. Acute toxicity in mice by intravenous administration, LD ^ q = 20 mg / kg. The substance shows an antireserpine effect in the ptosis test in mice; a dose of 4 mg / kg i.p. statistically significantly antagonizes reserpine-induced ptosis. Furthermore, the substance has a local anesthetic effect in guinea pig infiltration anesthesia test; at a concentration of 0.1 to 0.5% induces complete anesthesia in 50% of the animals. The substance is effective in the corneal anesthesia test in rabbits; at a concentration of 0.1 to 0.5% induces complete anesthesia of the rabbit eye cornea in 50% of the animals. Finally, it is also a spasmolytic because at concentrations of 1 to 10 µg / ml it inhibits the contraction of isolated rat duodenum induced by acetylcholine or barium chloride to 50%.

11- (Aminomethyl) -4-methoxy-6,11-dihydrodibenzo [b, e] thiepine was tested as the hydrochloride. Acute toxicity in mice by i.v. administration, LD ^ q = 15 mg / kg. Antireserpine activity is demonstrated in the reserpine ptosis assay in mice; the effective inhibitory dose is 3 mg / kg i.p. The spasmolytic effect on isolated rat duodenum is only manifested against barium chloride contractions; the effective concentration is 10 µg / ml,

11- (Methylaminomethyl) -6,11-dihydrodibenzo [b, e] thiepine was also tested as the hydrochloride. Acute oral toxicity in mice, LD ^ q = 67 mg / kg. The substance antagonizes the cataleptic activity of perfenazine in rats, suggesting its thymoleptic character, a median effective dose ΡΏ ^ θ = 10 to 30 mg / kg p.o.

4-Methoxy-11- (methylaminomethyl) -6,11-dihydrodibenzo [b, e] thiepine was also tested as the hydrochloride. Acute toxicity in mice, LD ^ q = 197.7 mg / kg p.o. The substance has a mild anti-cataleptic effect; antagonizes perfenazine-induced catalepsy in rats at an oral dose of 100 mg / kg.

11- (Dimethylaminomethyl) -6,11-dihydrodibenzo [b, e] thiepine was tested as the hydrochloride. Acute toxicity in mice, LD ^ q = 31.4 mg / kg i.v. The antireserpine effect is demonstrated in the reserpine ptosis assay in mice; ED = 2.5 mg / kg i. P. Local anesthetic effect in guinea pig infiltration anesthesia test, effective concentration is 0.1 to 0.5%. At the same concentrations, the substance is effective in the corneal anesthesia test in rabbits. Spasmolytic effect on acetylcholine and barium chloride contractions; the effective concentration is in both cases 1 to 10 µg / ml.

4-Methoxy-11- (dimethylaminomethyl) -6,11-dihydrodibenzo [b, e] thiepine was tested in the form of hydrochloride. Acute toxicity in mice LD ^ q = 38.4 mg / kg iv The substance has central depressant effects as reflected in the rotating rod test in mice; median effective dose causing ataxia ED ^ ₀ = 16.8 mg / kg iv symptom buffer effect is an effect on locomotor activity in mice in the jet test; Doses of 10 to 20 mg / kg iv reduce significant locomotor activity. At a dose of 100 g / kg po, the substance antagonizes perfenazine catalapsia in more than 50% of the rats in the experiment.

Compounds of formula I are obtained from acids of formula IX,

(II) wherein R is the same as in Formula I, by degradation using the Curtius method. This consists in converting the acids of formula II into chlorides by reaction with thionyl chloride, which react with sodium azide to give the corresponding acid azides, which in the raw state by heating with ethanol give the crystalline carbamates of formula III by rearrangement,

R

ch ₂ nhcooc ₂ h ₅ in which R denotes again the same as in formula I. Hydrolysis of these carbamates with ethanolic potassium hydroxide gives primary amines of formula I where R = R = H. Reduction of carbamates of formula IXI with lithium aluminum hydride in ether yields secondary amines of formula I, where?

R = H and R = CH3. Finally, methylation of said primary amines with formaldehyde and J 12 formic acid yields tertiary amines of formula I wherein R = R = CH 2. Of the starting acids of formula II, a substance with R = Η is known (V. Valenta et al., Colleet, Czeeh. Chem. Commun. 44, 2689, 1979, Pr. Pat. 1, 547, 207; 17, 154 and 68 / 3,656; Germany Pat. 1, 618.112; Chem. Abstract 70. 68 204, 1969 and 84, 180 092, 1976), and its chloride is also known ("V. Valenta et al., Cited) . The acid of formula II, wherein R = QCH-j, as well as its chloride, are novel and their preparation is described in the exemplary embodiment.

The invention provides salts of the compounds of formula I with pharmaceutically acceptable inorganic or organic acids which are more suitable than the free bases for pharmacological testing and for the preparation of dosage forms. Especially suitable salts have been found to be well-crystalline hydrochlorides which are water-soluble and are suitable for the preparation of injectable and oral dosage forms.

The identity of the end products according to the invention as well as the intermediates described in the examples were ensured both analytically and by all conventional spectral methods.

Examples

Example 1

- (Aminomethyl) -6,11-dihydrodibenzo [b, e] thiepine

A solution of 14.5 S 6,11-dihydrodibenzo [b, e] thiepine-11-acetic acid chloride (V. Valenta et al., Cited) in 70 ml acetone was added dropwise over 1 h to a stirred solution of 4.9 g sodium azide in 15 ml of water at 15 to 18 ° C. The mixture was stirred at room temperature for 1 h, poured into 700 g of ice-water and after stirring for 45 minutes it was filtered. 14.8 g of crude acid azide, melting at 73 DEG-76 DEG C., are decomposed. The entire amount of azide is added to 150 ml of ethanol and the mixture is refluxed under stirring for 3 hours. Then 70 ml of ethanol are distilled off, 6.5 ml of water are added dropwise and the mixture is left in the refrigerator overnight. 12.7 g (81%) of crude ethyl N- (6,11-dihydrodibenzo [b, e] thiepin-11-ylmethyl) carbamate crystallize out, which crystallizes from ethanol and melts in the pure state at 122-125 ° C.

A solution of 9) of the previous carbamate and 85 g of potassium hydroxide in 95 ml of ethanol is refluxed for 3 hours. It is then diluted with 70 ml of water and extracted with benzene. The separated benzene layer was shaken with 200 ml of 1M-H 2 SO 4, the precipitated solid sulfate was filtered off and added to the acidic aqueous layer of the filtrate. The suspension is basified with 50 ml of 5M-NaOH, the liberated base is extracted with benzene, the extract is dried over potassium carbonate and evaporated. 6.2 g (86%) of the crude desired base are obtained, m.p. 102-105 ° C. Crystallization from a mixture of benzene and cyclohexane gave the pure product, m.p. 105.5-106.5 ° C. Neutralization with hydrogen chloride in ethanol / ether gives the hydrochloride, which crystallizes from ethanol and melts in the pure state at 254-256 ° C with decomposition.

Example 2

- (Aminomethyl) -4-methoxy-6,11-dihydrodibenzo [b, e] thiepine

Similar to Example 1, 3.2 g of 4-methoxy-6,11-dihydrodibenzo [b, e] thiepin-11-acetic acid chloride in 15 ml of acetone are reacted with 0.98 g of sodium azide in 3 ml of water, to give 3.1 g of crude azide melting at 80-81 ° C with decomposition. This material was rearranged by boiling with 30 ml of ethanol to give 2.45 g (72%) of ethyl N- (4-methoxy-6,11-dihydrodibenzo [b, e] thiepin-11-ylmethyl) carbamate which crystallized from ethanol and melted at 158.5-160.5 ° C in pure state.

The obtained carbamate (2.05 g) is hydrolyzed with 17 g of potassium hydroxide in 18 ml of ethanol similar to the previous example to give 1.15 g (62%) of the desired solvate base, half of the benzene molecule, mp 67-71 ° C. (benzene). The hydrochloride prepared by neutralization crystallizes from aqueous ethanol and melts at 255-257 ° C.

The starting 4-methoxy-6,11-dihydrodibenzo [b, e] thiepine-11-acetic acid chloride is novel and is obtained, for example, by the following procedure.

A solution of 80 g of phthalide in 75.4 g of 2-methoxythiophenol (P. Mauthner, Ber. Deut. Chem. Ges.

39. 1348 (1906) was heated to 110 [deg.] C. and 115 g of potassium carbonate were added with stirring over 2 min. The mixture was stirred for 5 min, then heated to 125 ° C and left at this temperature for 1 h without stirring. After partial cooling, the mixture is diluted with 750 ml of hot water, the insoluble matter is filtered off and the filtrate is acidified with hydrochloric acid at 50 ° C. After cooling to 10 ° C, the crude product is isolated by filtration, washed with water and dried in vacuo. 128 g (87%) of 2- (2-methoxyphenylthiomethyl) benzoic acid melting at 116.5-120 ° C are obtained. Crystallization of the sample from aqueous ethanol yields the pure substance, mp 120-122 ° C.

A solution of 54.8 g of the preceding acid in 240 ml of toluene is added at 100 ° C to polyphosphoric acid prepared from 240 g of phosphoric pentoxide and 160 ml of 85% phosphoric acid. The mixture was stirred and refluxed for 2 hours, then quenched with 600 g of ice-water and the product was extracted with toluene. The extract was washed with 5% sodium hydroxide and water, dried over potassium carbonate and evaporated. 41.3 g (81%) of 4-methoxydibenzo [b, e] thiepin-11 (6H) -one, melting at 110 DEG-117 DEG C. are obtained. Crystallization from ethanol gave a pure substance of 8 t, mp 119.6-121 ° C.

To a stirred suspension of 137 g of the previous ketone in 1650 ml of ethanol at 45 ° C was slowly added 41 g of sodium borohydride and the mixture was refluxed for 4 h. The ethanol is evaporated under reduced pressure, the residue is diluted with water, the precipitated product is filtered, washed with water and dried. 127 g (92%) of 4-methoxy-6,11-dihydrodibenzo [b, e] thiepin-11-ol are obtained, which crystallizes from ethanol and melts at 166-167.5 ° C.

A suspension of 51.6 g of the preceding alcohol and 60 g of calcium chloride in 1000 ml of tetrahydrofuran is saturated with anhydrous hydrogen chloride for 1.5 hours at room temperature. The mixture was then filtered and the filtrate was evaporated. The residue was crystallized with a mixture of 80 ml of cyclohexane and 200 ml of petroleum ether. 52.0 g (94%) of almost pure 11-chloro-4-methoxy-6,11-dihydrodibenzo [b, e] thiole 217948 are obtained, melting at 98-105 ° C. the pure material is obtained by recrystallization from the same solvent mixture, m.p. 102-105 ° C.

A solution of 33.0 g of ethyl malonate in 70 ml of benzene was added dropwise over 40 minutes to a stirred suspension of 5.1 g of 80% sodium hydride in 560 ml of benzene. The mixture was heated to 60 ° C and a solution of 47.2 g of the pre-separated ehlordered derivative in 290 ml of benzene was added dropwise over 1 h. The mixture was refluxed for 3 h and allowed to stand overnight at room temperature. It is then washed with water, dried over magnesium sulphate and evaporated. The residue was dissolved in 50 ml of boiling methanol and the solution was allowed to crystallize; 49.5 g (72%) of crude diethyl (4-methoxy-6,11-dihydrodibenzo [b, e] thiepin-11-yl) malonate are obtained, melting at 95-102 ° C. the pure material is obtained by recrystallization from ethanol and melts at 102-104 ° C.

To a solution of 64.5 g of the preceding ester in 520 ml of ethanol was added a solution of 260 g of potassium hydroxide in 260 ml of water, and the mixture was refluxed for 6.5 hours. The ethanol was evaporated under reduced pressure, the residue was diluted with water, the solution was washed with benzene, filtered with charcoal and the filtrate acidified with hydrochloric acid. The crude product was isolated by filtration at 10 ° C and crystallized from aqueous methanol. 43.4 g (79%) of (4-methoxy-6,11-dihydrodibenzo [b, e] thiepin-11-yl) malonic acid are obtained, whose further crystallization from aqueous methanol is sometimes associated with a change in crystal modification and a sudden rise mp to 182-183 ° C, after drying mp 223-226 ° C.

A mixture of 23.0 g of the previous malonic acid, 30 ml of pyridine and 2.5 ml of piperidine was heated at reflux for 2.5 h. It is then poured into 120 ml of 5M-HCl, cooled to 3 ° C with ice, the product is filtered off with suction, washed with water and dried. 18.7 g (95%) of crude 4-methoxy-6,11-dihydrodibenzo [b, e] thiepine-11-acetic acid melting at 217-220 ° C is obtained. Crystallization from ethanol gave the pure product, mp 219.6-221.5 ° C. To a suspension of 30 g of the preceding acid in 150 ml of benzene was added a solution of 29 g of thionyl chloride in 50 ml of benzene, the mixture was stirred at 60-70 ° C for 2.5 h and refluxed for 0.5 h. It is then evaporated under reduced pressure and the residue is crystallized from a mixture of 50 ml of benzene and 40 ml of petroleum ether. 28 g (88%) of the desired 4-methoxy-6,11-dihydrodibenzo [b, e] thiepine-11-acetic acid chloride, m.p. 108 DEG-112 DEG C., are obtained.

Example 3

11- (Methylaminomethyl) -6,11-dihydrodibenzo [b, e] thiepine

A suspension of 4.6 g of ethyl N- (6,11-dihydrodibenzo [b, e] thiepin-11-ylmethyl) carbamate (see Example 1) in 200 ml of ether was added dropwise. to a stirred suspension of 3.4 g of lithium aluminum hydride in 80 ml of ether for 0.5 h and the mixture was refluxed for 8 h. After standing overnight, the mixture is quenched by the slow addition of 3.5 ml of 20% sodium hydroxide and 12 ml of water, stirred for 30 min with 3.5 g of potassium carbonate and filtered. Evaporation of the filtrate gave 3.4 g (88%) of the desired oily base which was converted into the hydrochloride by treatment with hydrogen chloride in ethanol / ether, mp 243-244 ° C (ethanol-ether).

Example 4

4-Methoxy-11- (methylaminomethyl) -6,1-dihydrodibenzo [b, e] thiepine

Ethyl N- (4-methoxy-6,11-dihydrodibenzo [b, e] thiepin-11-ylmethyl) carbamate (7.55 g) (see Example 2) was reduced similarly to the previous example with 5.0 g of hydride lithium aluminum in 370 ml of ether gave 5.0 g (80%) of the desired oily base which was converted to the hydrochloride, melting at 248-251 ° C (ethanol-ether).

Example 5

11- (Dimethylaminomethyl) -6,11-dihydrodibenzo [b, e] thiepine

A mixture of 7.3 g of 11- (aminomethyl) -6,11-dihydrodibenzo [b, e] thiepine (see Example 1), 11.6 g of formic acid, 17.2 ml of 32% formaldehyde and 16 ml of water is stirred 16 hours under reflux.

After cooling, the mixture was basified with 5M-NaOH and extracted with chloroform. Evaporation of the extract gave the crude base, which was dissolved in 15 ml of ethanol and neutralized with a solution of hydrogen chloride in ether. Upon standing and cooling, 7.2 g (78%) of the hydrochloride melting at 216 to 217 ^Q C (ethanol).

Example 6

4-Methoxy-11- (dimethylaminomethyl) -6,11-dihydrodibenzo [b, e] thiepine

11- (Aminomethyl) -4-methoxy-6,11-dihydrodibenzo [b, e] thiepine (2.7 g) (see Example 2) was methylated as above with a boiling mixture of 3.7 g formic acid, 6 ml 30% formaldehyde and 6 ml water. The desired base crystallizes from ethanol and melts at 124-125 ° C. Neutralization with hydrogen chloride in ethanol / ether gives the hydrochloride, m.p. 213 DEG-215 DEG C. (ethanol).

Claims (1)

OBJECT OF THE INVENTION (6,11-Dihydrodibenzo [b, e] thiepin-11-yl) methylamines of formula (I),